This invention relates to a process for preparing 4-substituted pyridines from other starting 4-substituted pyridines.
The ability to modify a particular pyridine derivative resulting in the formation of a second pyridine derivative is sometimes highly desirable. Particularly important modifications of pyridine derivatives are in three categories: (1) nucleophilic substitution of a suitable leaving group at the 2- or 4-position of the pyridine ring; (2) electrophilic substitution of an alkyl group at the 2- or 4-position of the pyridine ring; and (3) oxidative coupling of a pyridine derivative to produce a bipyridine.
The prior art describes many approaches to the solution of this general problem. For industrial purposes, the primary motivation for selecting the optimum pathway is usually a combination of availability of the first derivative and the cost effectiveness of the route used to convert it to the second derivative. This greatly reduces the number of options currently available. An appreciation for the inadequacy of the technology in this area, bearing in mind the above constraint, can be obtained from a brief survey of the literature.
The most expedient strategy for substituted pyridine transformations is direct exposure of the free base to the appropriate reagents. In the case of 2- or 4-picoline, activation of a methyl group toward electrophilic attack requires the use of very strong bases such as alkyl lithium compounds, sodamide or Lewis acids such as zinc chloride in combination with high temperature. Analogously, direct displacement of a suitable leaving group at the 2- or 4-position on the ring of a pyridine base demands extreme conditions. For example, conversion of 2-bromopyridine to 2-aminopyridine in 57% yield requires heating at 200.degree. C. with ammonium hydroxide under pressure. (Den Hertog et al, Rec. Trav. Chim. 51, 381 (1932).) Dimethylamine reacts with 4-chloropyridine under pressure at 150.degree. C. (L. Pentimalli, Gass. Chim. Ital., 94, 902 (1964).) Sodium or potassium amide and metal methyl anilides can be used successfully in etheral solvents or liquid ammonia but this approach is not practical on an industrial scale. (Hauser, J. Org. Chem., 15, 310 (1949).)
In addition to these considerations, accessibility of starting materials can also be a problem. Successful displacement reactions have been carried out in good yield with a variety of nucleophiles using N-pyridyl-4-pyridinium chloride hydrochloride or 4-phenoxypyridine as substrates. (D. Jerchel et al, Chem. Ber., 91, 1266 (1958).) These materials are not commercially available in bulk quantities which necessitates a separate synthesis. Moreover, the former substrate gives low yields in reactions with primary alkylamines. This is circumvented by using 4-phenoxy-pyridine; however, this material is even further removed from commercially available pyridine derivatives.
Another strategy which can be applied to the transformation of one pyridine derivative into another involves an activation-modification-deactivation sequence. Two methods of achieving this are known, namely, by taking advantage of the intermediacy of either the pyridine N-oxide of the initial pyridine derivative or its quaternary salt. It is well-documented that converting a pyridine compound to either of these two types of derivatives greatly enhances the reactivity of the 2- and 4-ring positions toward nucleophilic attack followed by expulsion of a leaving group if present. Furthermore, if an alkyl group is present at one of these positions, exposure of the quaternary salt to mild bases such as an alkylamine, or potassium ethoxide in the case of the N-oxide, is sufficient to initiate anhydro base formation resulting in a condensation or addition if an electrophile is present.
There are drawbacks to using a pyridine N-oxide in this scheme. These materials are usually less available than the pyridine precursor, and they require a synthesis and isolation prior to being carried through subsequent reactions. The degree of activation imparted by the N-oxide group is not as great as that of quaternary salt formation and reaction conditions, for example in substitution reactions with amines, are still vigorous. 4-chloropyridine-N-oxide undergoes reaction with diethylamine at 135.degree. C. in a sealed tube to produce the 4-substitution product in 47% yield, and the same reaction with morpholine occurs at 130.degree. C. to give a 53% yield of the analogous product. There is also the added obligation to reduce the N-oxide function in order to obtain the desired pyridine base.
Quaternary salt formation imparts the greatest reactivity to the 2- and 4-substituents of the pyridine ring. Consequently, more economical and available 4-pyridines, e.g., 4-cyanopyridine, can be quaternized with methyliodide, for example, and reacted with ammonia (Metzger et al, J. Org. Chem. 41 (15), 2621 (1978)) in preference to using a halopyridine. The conditions under which these salts are formed also offer the greatest potential for further reaction without isolation of intermediates. The milder reaction conditions possible as a result of greater reactivity combined with the ability to use these quaternary salts without isolation would present an attractive opportunity for processing one pyridine base into another if one final obstacle could be overcome. The difficulty is in the dequaternization of the newly formed pyridine quaternary salt.
The prior art describes several procedures for dealkylating the methyl quaternary salts of pyridine bases. These involve such reagents as triphenylphosphine/dimethylformamide at reflux (Aumann et al, J. Chem. Soc. Chem. Commun., 32 (1973), triphenylphosphine/acetonitrile (Kutney et al, Synth. Commun., 5 (2), 119 (1975) and diazabicyclononane/dimethylformamide or thiourea (Ho, Synth. Commun., 3, 99 (1973)). All of these methods have serious problems associated, with implementing them in a convenient and economical industrial preparation. The problems include cost of reagents, difficulty in recycling them and low yields and/or long reaction times in some cases.
A partial solution to the problems discussed above has been addressed in U.S. Pat. No. 4,158,093. A pyridine base is first quaternized with 2- or 4-vinylpyridine to give a pyridylethyl quaternary salt which is then converted into the quaternary salt of a new pyridine base by one of the three types of reactions described above. The new salt is subsequently converted to the desired pyridine base by dequaternization using sodium hydroxide. The co-product is vinylpyridine which is recovered and recycled.
The methodology, though an improvement over prior procedures, is not free of other disadvantages. For instance, the vinylpyridine co-product formed along with the desired pyridine derivative must be recovered and recycled in order to achieve a process which is economically practical. Over and above economic considerations, this can present operational problems. Vinylpyridines have physical properties similar to other pyridine bases. The most convenient method of separation is by distillation which is laborious in cases where the boiling point of the new pyridine base is close to that of the vinylpyridine produced. Even when this is not the case, avoiding this extra step is preferable.
Another drawback to this method is the use of large excesses (as high as 30 mole equivalents in one case) of sodium hydroxide in order to effect dequaternization of the intermediary pyridinium salt. This adds to the cost of the process by increased usage of raw materials, lowered product throughput and greater quantities of chemical waste to be treated and disposed of.
Consequently, the problem remains to provide a more advantageous process for preparing 4-substituted pyridines, preferably by a quaternization-modification-dequaternization sequence.